Re-Engineering Biologics Development

Research and development to discover new drugs, once done exclusively by large R&D departments in big pharmaceutical companies, is no longer the best model for drug discovery and development.

Smaller, nimbler companies are proving that through a combination of recent advancements in tools and technologies, pharmaceutical R&D can be done quickly, with more chances of success and faster time to market.

Oncobiologics is a newly formed company located in Cranbury, NJ that is proving that by combining the right technologies with the right people drug discovery and progression through Phase II clinical trials no longer has to be the time consuming and expensive process it once was.

The Company

As a relatively new company, Oncobiologics is proud of what they have accomplished in a short period of time. Self-described as a fully integrated biopharmaceutical company, the company has its own pipeline and intellectual property based on bi-specific single chain antibodies that leverage HSA (human serum albumin) bindings in the bloodstream.

The company’s business model is to quickly identify molecules that have potential therapeutic properties in one of the three main areas they are concentrating their discovery work in: oncology, immunology and immunooncology, and manufacture quantities sufficient to advance the compound through Phase II trials. The company can also offers its technologies, equipment and expertise to other companies who are developing compounds.

Proof of Concept Engine

Key to the company’s rapid discovery and development prowess is its high-tech proof of concept engine.

The biopharmaceutical industry has been wrestling with a complex but fundamental challenge for years: how to cost-effectively bring promising biologics candidates through the development pipeline to successful commercialization. The founders of Oncobiologics sought to take a fresh look at this challenge and to intentionally design their company to overcome it.

The company identified the following three principles as the cornerstones of its strategic vision:

1.Innovation in the discovery phase remains a critical driver for any biologics innovator, but discovery without a productive development path will condemn promising candidates.

2.A fundamental flaw in the conventional biologics business model is the enormous cost associated with funding failed assets. This expense drives up the cost of all candidates, and unduly burdens successful drugs with the excess cost of their failed predecessors. In addition, the enormous cost structure created by this entrenched problem results in an industry that is excessively cautious and capital constrained.

The solution is to identify failures sooner, especially prior to Phase III trials, which is where clinical costs can skyrocket. “Failing faster” also means failing cheaper.

The critical point for identifying failures is in the Proof of Concept (POC) stage, up until and through Phase II trials.

3.The cost and duration of clinical studies are determined by study design and clinical endpoints. Because these factors are largely beyond the control of the drug developer, the best available way to impact clinical trials is to reduce the time and cost associated with the preparation of the Chemistry, Manufacturing & Controls (CMC) package that dictates how the drug is to be produced. By eliminating the CMC package from the critical path (and doing so cost-effectively), the drug developer is able to move through clinical trials without avoidable disruption.

The Oncobiologics business model is built around a proprietary next generation antibody discovery platform and an integrated POC approach designed to achieve proof of concept with high speed, scientific rigor and low cost. The company’s rapid POC approach can take a molecule from “DNA to IND” within one year, providing the speed that is necessary to ensure that winning molecules can succeed, and that losing molecules can fail before they drag the company down with them.

A Four-Pronged Approach to Success

Oncobiologics has developed a four pronged approach to achieve this speed:

1)People: The Oncobiologics team is comprised of highly accomplished scientists and engineers with extensive experience at top tier pharma and biotech companies. Unlike a typical biotech start-up that may have a handful of discovery experts, but limited or no POC capabilities, Oncobiologics established an integrated team to capably carry its innovations forward. And while Oncobiologics can operate at the same scientific level as a top tier Pharma company, it remains entrepreneurial, agile and unburdened by the bureaucracy that can slow larger organizations. The talent and commitment of its team is the single most critical factor in Oncobiologics’ success.

2)Technology: Oncobiologics has established a state-of-the-art R&D facility designed with the latest technology and equipment. The facility was also designed to foster open collaboration, ensuring efficiency at every step of the POC process. Together, the technical capabilities enable high throughput CMC development with high scientific rigor. Key elements include:

IP based Discovery Technology

Oncobiologics has developed a next generation antibody platform designed to seek and penetrate tumors and other diseased tissue. The targeted scaffold design is ideal for oncology and immunology applications and is the basis for the company’s current therapeutic molecules. It is also capable of generating an extensive pipeline of additional molecules.

PROCESS TECHNOLOGY

Process Development Technology:

An essential component of biologics development is high-throughput screening. For the development and isolation of high producing recombinant cell lines, Oncobiologics employs Fluorescence Activated Cell Sorting (FACS). Bulk cell populations are either “enriched” for the top-producing clones, or sorted into microplates and monitored by the Celigo Cytometer for single cell per well. The use of these technologies together enables a logarithmic increase in the number of clones that are screened and reduces the time from DNA to a single high producing clone by 50% compared to conventional methods.

The clones, media, and physical process conditions best suited for larger scale manufacturing are next evaluated in micro-bioreactors. Recent advances in micro-bioreactor technology allow Oncobiologics to evaluate larger statistically designed experiments using a miniature version of a fully controlled production bioreactor. The miniaturized replica enables a rapid upstream development timeline with a rich data set.

Purification yields and product purity rely on the careful selection of modes of chromatography and optimal mobile phases. The use of microplate packed columns and liquid handling units enables a rapid evaluation of many modes of separation across multiple molecules. Oncobiologics utilizes this rich data set to develop robust process while minimizing the number of unique buffers and changes from product to product.

Conventional glass bioreactors and chromatography systems are used to finalize the process conditions before scaling to 200-L pilot scale.

The Formulation and Analytical Characterization teams use a variety of techniques andtechnologies to achieve rapid protein characterization to drive discovery, process, andproduct development.

Whether the product is a monoclonal antibody or a bispecific construct, protein engineering begins with the end in mind. The company’s analytical and formulations lab infrastructure was designed to ensure successful, well-characterized protein therapeutics. From project initiation, target product profiles are considered, which informs specifications and control strategy.

Throughout the Oncobiologics’ platform, multiple orthogonal techniques are used to obtain a complete assessment of product quality and stability. Characterization methods are used to achieve specific objectives, using protocols and approaches that will answer the question at hand, vs. running experiments to “check the boxes”. Stage-appropriate methods are employed that are fit for purpose and flexible for products in development.

One highlight of the analytical toolkit is the Orbitrap MS, which allows sequencing of monoclonal antibodies, accurately pinpointing the location and composition of post-translational modifications. UPLC systems provide high speed and high resolution chromatography, and are used for a variety of protein release and characterization methods.

The Orbitrap Mass Spectrometer is used in the analytical lab for accurate and preciseassessment of post-translational modifications.

An electronic lab notebook (ELN) system has been established from the company’s inception as a foundation for knowledge management.

Formulations development is fully integrated with analytics at Oncobiologics, based on the recognition that protein stability is best fostered by thorough protein characterization through multiple orthogonal techniques. High throughput configurations are used throughout for assessment of thermal and colloidal stability, enabling rapid preformulation screens with highly powered DoEs.

The Analytical and Formulations team works in close partnership with their Process Development colleagues on in-process stability, helping to refine process choices.

The team employs a pairing of in vitro and in silico work to augment characterization and guide the protein engineering of bispecific constructs.

BioAssay:

Ultimately, product quality comes down to biological activity. Oncobiologics recognizes this focus, and has built capabilities to assess and confirm product mechanism of action through a myriad of methodologies, including ELISAs, cell-based assays, surface plasmon resonance/Biacore, and microscopy.

The team recognizes that protein products are inherently heterogeneous, and that product development and commercialization requires classification of product variants as impurities (with changes in functionality) or substances (where differences have no impact). Oncobiologics delves into the structure/function relations in our protein products, and carefully develops physiologically relevant and interpretive bioassays, to characterize the impact of protein modifications in concert with other orthogonal methods. Advanced statistical approaches are used across all analytical methods and in the pooling of data to derive meaningful conclusions that secure the quality of products.

The team recognizes that protein products are inherently heterogeneous, and that product development and commercialization requires classification of product variants as impurities (with changes in functionality) or substances (where differences have no impact). Oncobiologics delves into the structure/function relations in our protein products, and carefully develops physiologically relevant and interpretive bioassays, to characterize the impact of protein modifications in concert with other orthogonal methods. Advanced statistical approaches are used across all analytical methods and in the pooling of data to derive meaningful conclusions that secure the quality of products.

cGMP Manufacturing Technology:

Oncobiologics is building a cGMP production facility composed exclusively of single-use-technology to manufacture its Phase I & II clinical supplies. The facility will feature a single-use 220 L scale bioreactor and will also include a 2000-L bioreactor for scale-up demonstration prior to commercial scale transfer. The facility is scheduled to be in production in the fourth quarter of 2012.

3)Integration:

The integration of technologies and scientific discipline is critical to achieving speed in a well-designed execution engine. Discovery, Process Development and Clinical Manufacturing is integrated to eliminate tech transfer and to ensure a smooth transition of the process into cGMP manufacturing. Oncobiologics has a well-integrated process development, analytical and formulation group in a project-management driven environment. Further, the electronic lab notebook system provides a paperless execution system designed for efficiency and speed.

4)Strategic Alliances:

While Oncobiologics has established extensive in-house capabilities, it also recognizes that certain expertise is best accessed through strategic partnerships. As a result, the company has entered several alliances to complement its core capabilities and to fill-in with expertise as needed. Current partners include Fox Chase Cancer Center, Biologics Consulting Group, Schiff Harden. Advent Engineering and Princeton Design Group.

The Future

With their combination of cutting edge technologies focusing on faster and more economical discovery and development of molecules, the company is well-postioned for growth, as Dr. Pankaj Mohan, the company's founder and CEO explains, "We think that our integrated model positions Oncobiologics well for bringing successful molecules through proof-of-concept. We have already attracted interest from some of the top people in the industry, so we are optimistic that this model is filling a void in the biopharm world."

And finally, in assessing the company's long-term prospects, Dr. Mohan gets right to the point, "Oncobiologics is designed to be a sustainable entity that can continue to generate promising candidates while working with industry partners to commercialize those candidates. We think this is the best way we can produce meaningful therapeutic advances while also creating a robust business that breathes new life into the pharma landscape."